on behalf of IGIGI InvestigatorsObjectives-To investigate the role of interleukin-1␤ (IL-1␤) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age. Methods and Results-A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the Ϫ511C/T IL-1␤ polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (Pϭ0.0020 in MI; Pϭ0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1␤ and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1␤ during cell stimulation resulted in a marked reduction of tissue factor activity expression. Key Words: risk factors Ⅲ genetics Ⅲ stroke Ⅲ myocardial infarction Ⅲ inflammation Ⅲ coagulation I ncreased levels of inflammatory markers are associated with ischemic vascular disease. [1][2][3][4] Inflammation has a relevant role in the initiation and progression of atherosclerosis; 5 however, it can also play a primary role in thrombosis development by activating the coagulation process. 6 Interleukin-1␤ (IL-1␤), a proinflammatory cytokine, stimulates the synthesis of tissue factor (TF) from monocytes and endothelial cells. 7,8 TF triggers activation of the coagulation cascade toward thrombus formation. 9 Inflammatory responses show a high interindividual variability and have been associated with polymorphisms in IL-1␤ gene; 10,11 the latter have also been related to the risk of several chronic inflammatory diseases. 11,12 We hypothesized that IL-1␤ gene polymorphisms might modulate the inflammation-triggered pathway of thrombus formation and the risk of ischemic arterial disease such as myocardial infarction (MI) and ischemic stroke. Patients with early-onset disease represent a subset of individuals in whom the impact of genes is more expressed and can be more easily identified. [13][14][15] Therefore, we investigated whether the risk of MI and ischemic stroke at young age is associated with polymorphisms in IL-1␤ gene and whether these polymorphisms can influence thrombosis by modulating the IL-1␤-mediated TF activation in response to inflammation. Conclusions--511C/T IL- Methods Study Population Patients With MIBetween May 1995 and July 2002, 430 patients Ͻ45 (males) or Ͻ50 (females) years of age admitted to cardiology centers (see the list in the Appendix) with a first episode of MI were consecutively included into the study. Acute MI was defined as resting chest pain lasting Ͼ30 minutes accompanied by ST-segment...

Abstract-Inflammation is a major contributing factor to atherosclerotic plaque development and ischemic heart disease.PTX3 is a long pentraxin that was recently found to be increased in patients with acute myocardial infarction. Because tissue factor (TF), the in vivo trigger of blood coagulation, plays a dominant role in thrombus formation after plaque rupture, we tested the possibility that PTX3 could modulate TF expression. Human umbilical vein endothelial cells, incubated with endotoxin (lipopolysaccharide) or the inflammatory cytokines interleukin-1␤ and tumor necrosis factor-␣, expressed TF. The presence of PTX3 increased TF activity and antigen severalfold in a dose-dependent fashion. PTX3 exerted its effect at the transcription level, inasmuch as the increased levels of TF mRNA, mediated by the stimuli, were enhanced in its presence. The increase in mRNA determined by PTX3 originated from an enhanced nuclear binding activity of the transacting factor c-Rel/p65, which was mediated by the agonists and measured by electrophoretic mobility shift assay. The mechanism underlying the increased c-Rel/p65 activity resided in an enhanced degradation of the c-Rel/p65 inhibitory protein IB␣. In the area of vascular injury, during the inflammatory response, cell-mediated fibrin deposition takes place. Our results suggest that PTX3, by increasing TF expression, potentially plays a role in thrombogenesis and ischemic vascular disease.

Angiotensin-converting enzyme (ACE) inhibitors reduce the risk of recurrent myocardial infarction in patients with left ventricular dysfunction. Tissue factor (TF), the initiator of blood coagulation, plays a pivotal role in arterial thrombosis that occurs after atherosclerotic plaque fissuring. Because monocytes synthesize TF and contain several components of the renin-angiotensin system, we investigated the possibility that ACE inhibitors could modulate monocyte TF expression. Mononuclear leukocytes from healthy volunteers were incubated with endotoxin in the presence or absence of different ACE inhibitors. Captopril reduced TF expression in endotoxin-stimulated mononuclear leukocytes, as measured by a 1-stage clotting assay and ELISA analysis, by approximately 60%. The effect was dose-dependent and was attributable to ACE inhibition, given that other ACE inhibitors, such as idrapril or fosinopril, and losartan, an antagonist of the angiotensin II AT(1) receptor, caused a comparable reduction in TF activity. Reverse transcriptase-polymerase chain reaction indicated that endotoxin-mediated increased levels of TF mRNA were inhibited by ACE inhibitors. Moreover, endotoxin-induced nuclear factor-kappaB translocation to the promoter region of the gene encoding for TF was markedly inhibited by captopril. The finding that ACE inhibitors and angiotensin II AT(1) antagonists can potentially modulate TF expression by mononuclear cells has important biological and therapeutic implications for the evolution of thrombi. Our results suggest that the anti-ischemic effect of these drugs might be explained, at least in part, by their ability to reduce TF expression in monocytes.